HIV-1 associated neuropathogenesis is characterized by two distinct observations. The first concerns the notable cognitive and motor dysfunction in HIV-1 infected individuals. The second relates to the lack of infection of neurons by HIV-1. This suggests that the dementia in AIDS patients might be the result of a combination of both direct and indirect effects of HIV-1 encoded proteins (Env, Tat, Nef and Vpr) and host cellular factors. The mechanisms underlying the onset and progression of dementia are poorly understood. The goal of this application is to elucidate the contribution of HIV-1 Vpr to neuropathogenesis. In the infected individuals, Vpr is present in cell-associated, virion-associated and cell and virion-free forms. Further, the ability to traverse through cell membrane endows Vpr the potential to cause damage directly in uninfected bystanders such as neurons. Furthermore, Vpr is also known to indirectly dysregulate bystander cells through cellular factors released from infected target cells. Based on this, we hypothesize that Vpr has the potential to contribute to neuronal apoptosis and dysfunction. To elucidate the molecular events underlying dementia, we propose to analyze the effects of Vpr using appropriate human primary cells in culture as a model. To achieve these goals we propose to: (i) determine the mechanism(s) involved in Vpr mediated neuronal loss and dysfunction directly;(ii) identify the cellular cofactors and neuroinflammatory molecules differentially regulated by Vpr in target cells;and (iii) identify the structure-function relation of Vpr to neuropathogenesis using naturally occurring Vpr variants from CNS compartment. PUBLIC HEALTH RELEVANCE: Dramatic improvements in treating HIV-1 infected individuals have been attained with Highly Active Anti-Retroviral Therapy (HAART), and despite the availability of HAART, neurocognitive disorders affect 50-70% of the HIV-1 infected individuals. High incidence of HIV-Associated Dementia (HAD) is due to the neuronal dysfunction caused by the viral proteins as well as the inflammatory factors released by the infected cells into the local environment. Therefore, a combination therapy targeting both viral and neuroinflammatory factors would be desirable. This study focuses on understanding the role of viral and host cellular factors in neuropathogenesis toward identifying novel targets and designing new therapeutics against HIV-1 in the central nervous system.